Skip to main content
SpringerLink
Log in

Advances in Treatment of Drug-Resistant Pulmonary TB: What Is the Latest Approach to Treat Drug-Resistant Pulmonary TB?

  • Chapter
  • First Online:
Pulmonary Tuberculosis and Its Prevention

  • 265 Accesses

Abstract

Drug-resistant strains of Mycobacterium tuberculosis continue to pose a major threat to global TB control. Despite the availability of curative anti-TB therapy, inappropriate and inadequate treatment, as well as unchecked transmission, has allowed drug-resistant strains of M. tuberculosis to spread globally. The World Health Organization (WHO) estimated that there were 465,000 cases of multidrug-resistant tuberculosis (MDR-TB)/rifampin-resistance tuberculosis (RR-TB) in 2019 and only 44% were detected and notified. Treatment of MDR-TB is challenging because it has traditionally required the administration of multiple anti-TB drugs, many associated with significant adverse reactions, for a prolonged duration. Globally, treatment outcomes remain poor with low treatment success and relatively high rates of treatment failure and lost to follow-up. Recently, there have been major advances in the treatment of MDR/RR-TB such as the availability of all oral regimens and shorter course regimens with high treatment success. This chapter will review the current approach to treatment of drug-resistant TB.

This is a preview of subscription content, log in via an institution to check access.

Access this chapter

Log in via an institution
Chapter
USD 29.95
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
USD 84.99
Price excludes VAT (USA)
  • Available as EPUB and PDF
  • Read on any device
  • Instant download
  • Own it forever
Hardcover Book
USD 109.99
Price excludes VAT (USA)
  • Durable hardcover edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info

Tax calculation will be finalised at checkout

Purchases are for personal use only

Institutional subscriptions

References

  1. World Health Organization. Global tuberculosis report, 2020. Geneva: World Health Organization; 2020.

    Google Scholar 

  2. World Health Organization. Global tuberculosis report, 2021. Geneva: World Health Organization; 2021.

    Google Scholar 

  3. World Health Organization. Report of the meeting of the WHO Global Task Force on XDR-TB. Geneva: World Health Organization; 2006.

    Google Scholar 

  4. Roelens M, Battista Migliori G, Rozanova L, Estill J, Campbell JR, Cegielski JP, et al. Evidence-based definition for extensively drug-resistant tuberculosis. Am J Respir Crit Care Med. 2021;204(6):713–22. https://doi.org/10.1164/rccm.202009-3527OC.

    Article  CAS  PubMed  Google Scholar 

  5. Gegia M, Winters N, Benedetti A, van Soolingen D, Menzies D. Treatment of isoniazid-resistant tuberculosis with first-line drugs: a systematic review and meta-analysis. Lancet Infect Dis. 2017;17(2):223–34. https://doi.org/10.1016/S1473-3099(16)30407-8.

    Article  CAS  PubMed  Google Scholar 

  6. Nahid P, Mase SR, Migliori GB, Sotgiu G, Bothamley GH, Brozek JL, et al. Treatment of drug-resistant tuberculosis. An official ATS/CDC/ERS/IDSA clinical practice guideline. Am J Respir Crit Care Med. 2019;200(10):e93–e142. https://doi.org/10.1164/rccm.201909-1874ST.

    Article  PubMed  PubMed Central  Google Scholar 

  7. World Health Organization. WHO consolidated guidelines on tuberculosis. Module 4: treatment—drug-resistant tuberculosis treatment. Geneva: World Health Organization; 2021.

    Google Scholar 

  8. Iseman MD. Treatment of multidrug-resistant tuberculosis. N Engl J Med. 1993;329(11):784–91. https://doi.org/10.1056/NEJM199309093291108.

    Article  CAS  PubMed  Google Scholar 

  9. World Health Organization. WHO treatment guidelines for drug-resistant tuberculosis, 2016 update. Geneva: World Health Organization; 2016.

    Google Scholar 

  10. Migliori GB, Lange C, Girardi E, Centis R, Besozzi G, Kliiman K, et al. Fluoroquinolones: are they essential to treat multidrug-resistant tuberculosis? Eur Respir J. 2008;31(4):904–5. https://doi.org/10.1183/09031936.00159807.

    Article  CAS  PubMed  Google Scholar 

  11. Caminero JA, Scardigli A. Classification of antituberculosis drugs: a new proposal based on the most recent evidence. Eur Respir J. 2015;46(4):887–93. https://doi.org/10.1183/13993003.00432-2015.

    Article  PubMed  Google Scholar 

  12. Chan ED, Laurel V, Strand MJ, Chan JF, Huynh ML, Goble M, et al. Treatment and outcome analysis of 205 patients with multidrug-resistant tuberculosis. Am J Respir Crit Care Med. 2004;169(10):1103–9. https://doi.org/10.1164/rccm.200308-1159OC.

    Article  PubMed  Google Scholar 

  13. Chiang CY, Enarson DA, Yu MC, Bai KJ, Huang RM, Hsu CJ, et al. Outcome of pulmonary multidrug-resistant tuberculosis: a 6-yr follow-up study. Eur Respir J. 2006;28(5):980–5. https://doi.org/10.1183/09031936.06.00125705.

    Article  PubMed  Google Scholar 

  14. Kam KM, Yip CW, Cheung TL, Tang HS, Leung OC, Chan MY. Stepwise decrease in moxifloxacin susceptibility amongst clinical isolates of multidrug-resistant Mycobacterium tuberculosis: correlation with ofloxacin susceptibility. Microb Drug Resist. 2006;12(1):7–11. https://doi.org/10.1089/mdr.2006.12.7.

    Article  CAS  PubMed  Google Scholar 

  15. Cheng AF, Yew WW, Chan EW, Chin ML, Hui MM, Chan RC. Multiplex PCR amplimer conformation analysis for rapid detection of gyrA mutations in fluoroquinolone-resistant Mycobacterium tuberculosis clinical isolates. Antimicrob Agents Chemother. 2004;48(2):596–601.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Zignol M, Dean AS, Alikhanova N, Andres S, Cabibbe AM, Cirillo DM, et al. Population-based resistance of Mycobacterium tuberculosis isolates to pyrazinamide and fluoroquinolones: results from a multicountry surveillance project. Lancet Infect Dis. 2016;16(10):1185–92. https://doi.org/10.1016/S1473-3099(16)30190-6.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Johnson JL, Hadad DJ, Boom WH, Daley CL, Peloquin CA, Eisenach KD, et al. Early and extended early bactericidal activity of levofloxacin, gatifloxacin and moxifloxacin in pulmonary tuberculosis. Int J Tuberc Lung Dis. 2006;10(6):605–12.

    CAS  PubMed  Google Scholar 

  18. Peloquin CA, Hadad DJ, Molino LP, Palaci M, Boom WH, Dietze R, et al. Population pharmacokinetics of levofloxacin, gatifloxacin, and moxifloxacin in adults with pulmonary tuberculosis. Antimicrob Agents Chemother. 2008;52(3):852–7. https://doi.org/10.1128/AAC.01036-07.

    Article  CAS  PubMed  Google Scholar 

  19. Lee J, Lee CH, Kim DK, Yoon HI, Kim JY, Lee SM, et al. Retrospective comparison of levofloxacin and moxifloxacin on multidrug-resistant tuberculosis treatment outcomes. Korean J Intern Med. 2011;26(2):153–9. https://doi.org/10.3904/kjim.2011.26.2.153.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Diacon AH, Pym A, Grobusch M, Patientia R, Rustomjee R, Page-Shipp L, et al. The diarylquinoline TMC207 for multidrug-resistant tuberculosis. N Engl J Med. 2009;360(23):2397–405. https://doi.org/10.1056/NEJMoa0808427.

    Article  CAS  PubMed  Google Scholar 

  21. Diacon AH, Donald PR, Pym A, Grobusch M, Patientia RF, Mahanyele R, et al. Randomized pilot trial of eight weeks of bedaquiline (TMC207) treatment for multidrug-resistant tuberculosis: long-term outcome, tolerability, and effect on emergence of drug resistance. Antimicrob Agents Chemother. 2012;56(6):3271–6. https://doi.org/10.1128/AAC.06126-11.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Pym AS, Diacon AH, Tang SJ, Conradie F, Danilovits M, Chuchottaworn C, et al. Bedaquiline in the treatment of multidrug- and extensively drug-resistant tuberculosis. Eur Respir J. 2016;47(2):564–74. https://doi.org/10.1183/13993003.00724-2015.

    Article  CAS  PubMed  Google Scholar 

  23. Borisov SE, Dheda K, Enwerem M, Romero Leyet R, D’Ambrosio L, Centis R, et al. Effectiveness and safety of bedaquiline-containing regimens in the treatment of MDR- and XDR-TB: a multicentre study. Eur Respir J. 2017;49(5):1700387. https://doi.org/10.1183/13993003.00387-2017.

    Article  CAS  PubMed  Google Scholar 

  24. Sotgiu G, Centis R, D’Ambrosio L, Alffenaar JW, Anger HA, Caminero JA, et al. Efficacy, safety and tolerability of linezolid containing regimens in treating MDR-TB and XDR-TB: systematic review and meta-analysis. Eur Respir J. 2012;40(6):1430–42. https://doi.org/10.1183/09031936.00022912.

    Article  CAS  PubMed  Google Scholar 

  25. Cox H, Ford N. Linezolid for the treatment of complicated drug-resistant tuberculosis: a systematic review and meta-analysis. Int J Tuberc Lung Dis. 2012;16(4):447–54. https://doi.org/10.5588/ijtld.11.0451.

    Article  CAS  PubMed  Google Scholar 

  26. Conradie F, Diacon AH, Ngubane N, Howell P, Everitt D, Crook AM, et al. Treatment of highly drug-resistant pulmonary tuberculosis. N Engl J Med. 2020;382(10):893–902. https://doi.org/10.1056/NEJMoa1901814.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Dooley KE, Obuku EA, Durakovic N, Belitsky V, Mitnick C, Nuermberger EL, et al. World Health Organization group 5 drugs for the treatment of drug-resistant tuberculosis: unclear efficacy or untapped potential? J Infect Dis. 2013;207(9):1352–8. https://doi.org/10.1093/infdis/jis460.

    Article  CAS  PubMed  Google Scholar 

  28. Xu J, Lu Y, Fu L, Zhu H, Wang B, Mdluli K, et al. In vitro and in vivo activity of clofazimine against Mycobacterium tuberculosis persisters. Int J Tuberc Lung Dis. 2012;16(8):1119–25. https://doi.org/10.5588/ijtld.11.0752.

    Article  CAS  PubMed  Google Scholar 

  29. Dey T, Brigden G, Cox H, Shubber Z, Cooke G, Ford N. Outcomes of clofazimine for the treatment of drug-resistant tuberculosis: a systematic review and meta-analysis. J Antimicrob Chemother. 2013;68(2):284–93. https://doi.org/10.1093/jac/dks389.

    Article  CAS  PubMed  Google Scholar 

  30. Xu HB, Jiang RH, Xiao HP. Clofazimine in the treatment of multidrug-resistant tuberculosis. Clin Microbiol Infect. 2012;18(11):1104–10. https://doi.org/10.1111/j.1469-0691.2011.03716.x.

    Article  CAS  PubMed  Google Scholar 

  31. Dalcolmo M, Gayoso R, Sotgiu G, D’Ambrosio L, Rocha JL, Borga L, et al. Effectiveness and safety of clofazimine in multidrug-resistant tuberculosis: a nationwide report from Brazil. Eur Respir J. 2017;49(3):1602445. https://doi.org/10.1183/13993003.02445-2016.

    Article  CAS  PubMed  Google Scholar 

  32. Van Deun A, Maug AK, Salim MA, Das PK, Sarker MR, Daru P, et al. Short, highly effective, and inexpensive standardized treatment of multidrug-resistant tuberculosis. Am J Respir Crit Care Med. 2010;182(5):684–92. https://doi.org/10.1164/rccm.201001-0077OC.

    Article  PubMed  Google Scholar 

  33. Van Deun A, Salim MA, Das AP, Bastian I, Portaels F. Results of a standardised regimen for multidrug-resistant tuberculosis in Bangladesh. Int J Tuberc Lung Dis. 2004;8(5):560–7.

    PubMed  Google Scholar 

  34. Tang S, Yao L, Hao X, Liu Y, Zeng L, Liu G, et al. Clofazimine for the treatment of multidrug-resistant tuberculosis: prospective, multicenter, randomized controlled study in China. Clin Infect Dis. 2015;60(9):1361–7. https://doi.org/10.1093/cid/civ027.

    Article  PubMed  Google Scholar 

  35. Caminero JA, Sotgiu G, Zumla A, Migliori GB. Best drug treatment for multidrug-resistant and extensively drug-resistant tuberculosis. Lancet Infect Dis. 2010;10(9):621–9. https://doi.org/10.1016/S1473-3099(10)70139-0.

    Article  CAS  PubMed  Google Scholar 

  36. Epstein IG, Nair KG, Boyd LJ, Auspitz P. Cycloserine-isoniazid combination therapy in virgin cases of pulmonary tuberculosis. Dis Chest. 1958;33(4):371–81.

    Article  CAS  PubMed  Google Scholar 

  37. Angel JH, Bhatia AL, Devadatta S, Fox W, Janardhanam B, Radhakrishna S, et al. A controlled comparison of cycloserine plus ethionamide with cycloserine plus thiacetazone in patients with active pulmonary tuberculosis despite prolonged previous chemotherapy. Tubercle. 1963;44:215–24.

    Article  CAS  PubMed  Google Scholar 

  38. Shi W, Zhang X, Jiang X, Yuan H, Lee JS, Barry CE 3rd, et al. Pyrazinamide inhibits trans-translation in Mycobacterium tuberculosis. Science. 2011;333(6049):1630–2. https://doi.org/10.1126/science.1208813.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Mitnick C, Bayona J, Palacios E, Shin S, Furin J, Alcantara F, et al. Community-based therapy for multidrug-resistant tuberculosis in Lima, Peru. N Engl J Med. 2003;348(2):119–28. https://doi.org/10.1056/NEJMoa022928.

    Article  PubMed  Google Scholar 

  40. Migliori GB, Besozzi G, Girardi E, Kliiman K, Lange C, Toungoussova OS, et al. Clinical and operational value of the extensively drug-resistant tuberculosis definition. Eur Respir J. 2007;30(4):623–6. https://doi.org/10.1183/09031936.00077307.

    Article  CAS  PubMed  Google Scholar 

  41. World Health Organization. Guidelines for the programmatic management of drug-reisistant tuberculosis. Geneva: World Health Organization; 2011.

    Google Scholar 

  42. Dooley KE, Mitnick CD, Ann DeGroote M, Obuku E, Belitsky V, Hamilton CD, et al. Old drugs, new purpose: retooling existing drugs for optimized treatment of resistant tuberculosis. Clin Infect Dis. 2012;55(4):572–81. https://doi.org/10.1093/cid/cis487.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. World Health Organization. Guidelines for the programmatic management of drug-resistant tuberculosis. Geneva: World Health Organization; 2008.

    Google Scholar 

  44. Gler MT, Skripconoka V, Sanchez-Garavito E, Xiao H, Cabrera-Rivero JL, Vargas-Vasquez DE, et al. Delamanid for multidrug-resistant pulmonary tuberculosis. N Engl J Med. 2012;366(23):2151–60. https://doi.org/10.1056/NEJMoa1112433.

    Article  CAS  PubMed  Google Scholar 

  45. von Groote-Bidlingmaier F, Patientia R, Sanchez E, Balanag V Jr, Ticona E, Segura P, et al. Efficacy and safety of delamanid in combination with an optimised background regimen for treatment of multidrug-resistant tuberculosis: a multicentre, randomised, double-blind, placebo-controlled, parallel group phase 3 trial. Lancet Respir Med. 2019;7(3):249–59. https://doi.org/10.1016/S2213-2600(18)30426-0.

    Article  Google Scholar 

  46. Chang KC, Chung-Ching Leung E, Law WS, Leung WM, Tai LB, Lee SN, et al. Early experience with delamanid-containing regimens in the treatment of complicated multidrug-resistant tuberculosis in Hong Kong. Eur Respir J. 2018;51(6):1800159. https://doi.org/10.1183/13993003.00159-2018.

    Article  CAS  PubMed  Google Scholar 

  47. Kuksa L, Barkane L, Hittel N, Gupta R. Final treatment outcomes of multidrug- and extensively drug-resistant tuberculosis patients in Latvia receiving delamanid-containing regimens. Eur Respir J. 2017;50(5):1701105. https://doi.org/10.1183/13993003.01105-2017.

    Article  CAS  PubMed  Google Scholar 

  48. Hewison C, Ferlazzo G, Avaliani Z, Hayrapetyan A, Jonckheere S, Khaidarkhanova Z, et al. Six-month response to delamanid treatment in MDR TB patients. Emerg Infect Dis. 2017;23(10):1746–8. https://doi.org/10.3201/eid2310.170468.

    Article  PubMed  PubMed Central  Google Scholar 

  49. Hafkin J, Hittel N, Martin A, Gupta R. Early outcomes in MDR-TB and XDR-TB patients treated with delamanid under compassionate use. Eur Respir J. 2017;50(1):1700311. https://doi.org/10.1183/13993003.00311-2017.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  50. Chambers HF, Turner J, Schecter GF, Kawamura M, Hopewell PC. Imipenem for treatment of tuberculosis in mice and humans. Antimicrob Agents Chemother. 2005;49(7):2816–21. https://doi.org/10.1128/AAC.49.7.2816-2821.2005.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  51. De Lorenzo S, Alffenaar JW, Sotgiu G, Centis R, D’Ambrosio L, Tiberi S, et al. Efficacy and safety of meropenem-clavulanate added to linezolid-containing regimens in the treatment of MDR-/XDR-TB. Eur Respir J. 2013;41(6):1386–92. https://doi.org/10.1183/09031936.00124312.

    Article  CAS  PubMed  Google Scholar 

  52. Tiberi S, Payen MC, Sotgiu G, D’Ambrosio L, Alarcon Guizado V, Alffenaar JW, et al. Effectiveness and safety of meropenem/clavulanate-containing regimens in the treatment of MDR- and XDR-TB. Eur Respir J. 2016;47(4):1235–43. https://doi.org/10.1183/13993003.02146-2015.

    Article  CAS  PubMed  Google Scholar 

  53. Tiberi S, Sotgiu G, D’Ambrosio L, Centis R, Abdo Arbex M, Alarcon Arrascue E, et al. Comparison of effectiveness and safety of imipenem/clavulanate- versus meropenem/clavulanate-containing regimens in the treatment of MDR- and XDR-TB. Eur Respir J. 2016;47(6):1758–66. https://doi.org/10.1183/13993003.00214-2016.

    Article  CAS  PubMed  Google Scholar 

  54. Tiberi S, Sotgiu G, D’Ambrosio L, Centis R, Arbex MA, Alarcon Arrascue E, et al. Effectiveness and safety of imipenem-clavulanate added to an optimized background regimen (OBR) versus OBR control regimens in the treatment of multidrug-resistant and extensively drug-resistant tuberculosis. Clin Infect Dis. 2016;62(9):1188–90. https://doi.org/10.1093/cid/ciw088.

    Article  PubMed  Google Scholar 

  55. Tiberi S, D’Ambrosio L, De Lorenzo S, Viggiani P, Centis R, Sotgiu G, et al. Ertapenem in the treatment of multidrug-resistant tuberculosis: first clinical experience. Eur Respir J. 2016;47(1):333–6. https://doi.org/10.1183/13993003.01278-2015.

    Article  CAS  PubMed  Google Scholar 

  56. Crowle AJ, Sbarbaro JA, Judson FN, Douvas GS, May MH. Inhibition by streptomycin of tubercle bacilli within cultured human macrophages. Am Rev Respir Dis. 1984;130(5):839–44. https://doi.org/10.1164/arrd.1984.130.5.839.

    Article  CAS  PubMed  Google Scholar 

  57. Caminero JA, World Health O, American Thoracic S, British Thoracic S. Treatment of multidrug-resistant tuberculosis: evidence and controversies. Int J Tuberc Lung Dis. 2006;10(8):829–37.

    Google Scholar 

  58. Heifets L, Lindholm-Levy P. Comparison of bactericidal activities of streptomycin, amikacin, kanamycin, and capreomycin against Mycobacterium avium and M. tuberculosis. Antimicrob Agents Chemother. 1989;33(8):1298–301.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  59. Seddon JA, Godfrey-Faussett P, Jacobs K, Ebrahim A, Hesseling AC, Schaaf HS. Hearing loss in patients on treatment for drug-resistant tuberculosis. Eur Respir J. 2012;40(5):1277–86. https://doi.org/10.1183/09031936.00044812.

    Article  PubMed  Google Scholar 

  60. Reuter A, Tisile P, von Delft D, Cox H, Cox V, Ditiu L, et al. The devil we know: is the use of injectable agents for the treatment of MDR-TB justified? Int J Tuberc Lung Dis. 2017;21(11):1114–26. https://doi.org/10.5588/ijtld.17.0468.

    Article  CAS  PubMed  Google Scholar 

  61. Georghiou SB, Magana M, Garfein RS, Catanzaro DG, Catanzaro A, Rodwell TC. Evaluation of genetic mutations associated with Mycobacterium tuberculosis resistance to amikacin, kanamycin and capreomycin: a systematic review. PLoS One. 2012;7(3):e33275. https://doi.org/10.1371/journal.pone.0033275.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  62. Alangaden GJ, Kreiswirth BN, Aouad A, Khetarpal M, Igno FR, Moghazeh SL, et al. Mechanism of resistance to amikacin and kanamycin in Mycobacterium tuberculosis. Antimicrob Agents Chemother. 1998;42(5):1295–7.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  63. Kruuner A, Jureen P, Levina K, Ghebremichael S, Hoffner S. Discordant resistance to kanamycin and amikacin in drug-resistant Mycobacterium tuberculosis. Antimicrob Agents Chemother. 2003;47(9):2971–3.

    Article  PubMed  PubMed Central  Google Scholar 

  64. Maus CE, Plikaytis BB, Shinnick TM. Molecular analysis of cross-resistance to capreomycin, kanamycin, amikacin, and viomycin in Mycobacterium tuberculosis. Antimicrob Agents Chemother. 2005;49(8):3192–7. https://doi.org/10.1128/AAC.49.8.3192-3197.2005.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  65. Mathys V, Wintjens R, Lefevre P, Bertout J, Singhal A, Kiass M, et al. Molecular genetics of para-aminosalicylic acid resistance in clinical isolates and spontaneous mutants of Mycobacterium tuberculosis. Antimicrob Agents Chemother. 2009;53(5):2100–9. https://doi.org/10.1128/AAC.01197-08.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  66. PARA-AMINOSALICYLIC acid treatment in pulmonary tuberculosis. Am Rev Tuberc. 1950;61(5):597–612.

    Google Scholar 

  67. Gagneux S, Burgos MV, DeRiemer K, Encisco A, Munoz S, Hopewell PC, et al. Impact of bacterial genetics on the transmission of isoniazid-resistant Mycobacterium tuberculosis. PLoS Pathog. 2006;2(6):e61. https://doi.org/10.1371/journal.ppat.0020061.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  68. Cambau E, Viveiros M, Machado D, Raskine L, Ritter C, Tortoli E, et al. Revisiting susceptibility testing in MDR-TB by a standardized quantitative phenotypic assessment in a European multicentre study. J Antimicrob Chemother. 2015;70(3):686–96. https://doi.org/10.1093/jac/dku438.

    Article  CAS  PubMed  Google Scholar 

  69. Morlock GP, Metchock B, Sikes D, Crawford JT, Cooksey RC. ethA, inhA, and katG loci of ethionamide-resistant clinical Mycobacterium tuberculosis isolates. Antimicrob Agents Chemother. 2003;47(12):3799–805.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  70. Banerjee A, Dubnau E, Quemard A, Balasubramanian V, Um KS, Wilson T, et al. inhA, a gene encoding a target for isoniazid and ethionamide in Mycobacterium tuberculosis. Science. 1994;263(5144):227–30.

    Article  CAS  PubMed  Google Scholar 

  71. Warren RM, Streicher EM, Gey van Pittius NC, Marais BJ, van der Spuy GD, Victor TC, et al. The clinical relevance of Mycobacterial pharmacogenetics. Tuberculosis (Edinb). 2009;89(3):199–202. https://doi.org/10.1016/j.tube.2009.03.001.

    Article  CAS  PubMed  Google Scholar 

  72. Rieder HL, Van Deun A. Rationale for high-dose isoniazid in the treatment of multidrug-resistant tuberculosis. Int J Tuberc Lung Dis. 2017;21(1):123–4. https://doi.org/10.5588/ijtld.16.0619.

    Article  PubMed  Google Scholar 

  73. Cynamon MH, Zhang Y, Harpster T, Cheng S, DeStefano MS. High-dose isoniazid therapy for isoniazid-resistant murine Mycobacterium tuberculosis infection. Antimicrob Agents Chemother. 1999;43(12):2922–4.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  74. Katiyar SK, Bihari S, Prakash S, Mamtani M, Kulkarni H. A randomised controlled trial of high-dose isoniazid adjuvant therapy for multidrug-resistant tuberculosis. Int J Tuberc Lung Dis. 2008;12(2):139–45.

    CAS  PubMed  Google Scholar 

  75. Caminero JA, Piubello A, Scardigli A, Migliori GB. Proposal for a standardised treatment regimen to manage pre- and extensively drug-resistant tuberculosis cases. Eur Respir J. 2017;50(1):1700648. https://doi.org/10.1183/13993003.00648-2017.

    Article  CAS  PubMed  Google Scholar 

  76. Schaaf HS, Moll AP, Dheda K. Multidrug- and extensively drug-resistant tuberculosis in Africa and South America: epidemiology, diagnosis and management in adults and children. Clin Chest Med. 2009;30(4):667–83, vii-viii. https://doi.org/10.1016/j.ccm.2009.08.019.

    Article  PubMed  Google Scholar 

  77. Stover CK, Warrener P, VanDevanter DR, Sherman DR, Arain TM, Langhorne MH, et al. A small-molecule nitroimidazopyran drug candidate for the treatment of tuberculosis. Nature. 2000;405(6789):962–6. https://doi.org/10.1038/35016103.

    Article  CAS  PubMed  Google Scholar 

  78. Singh R, Manjunatha U, Boshoff HI, Ha YH, Niyomrattanakit P, Ledwidge R, et al. PA-824 kills nonreplicating Mycobacterium tuberculosis by intracellular NO release. Science. 2008;322(5906):1392–5. https://doi.org/10.1126/science.1164571.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  79. Manjunatha U, Boshoff HI, Barry CE. The mechanism of action of PA-824: novel insights from transcriptional profiling. Commun Integr Biol. 2009;2(3):215–8. https://doi.org/10.4161/cib.2.3.7926.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  80. Diacon AH, Dawson R, von Groote-Bidlingmaier F, Symons G, Venter A, Donald PR, et al. 14-day bactericidal activity of PA-824, bedaquiline, pyrazinamide, and moxifloxacin combinations: a randomised trial. Lancet. 2012;380(9846):986–93. https://doi.org/10.1016/S0140-6736(12)61080-0.

    Article  CAS  PubMed  Google Scholar 

  81. Dawson R, Diacon AH, Everitt D, van Niekerk C, Donald PR, Burger DA, et al. Efficiency and safety of the combination of moxifloxacin, pretomanid (PA-824), and pyrazinamide during the first 8 weeks of antituberculosis treatment: a phase 2b, open-label, partly randomised trial in patients with drug-susceptible or drug-resistant pulmonary tuberculosis. Lancet. 2015;385(9979):1738–47. https://doi.org/10.1016/S0140-6736(14)62002-X.

    Article  CAS  PubMed  Google Scholar 

  82. Franke MF, Khan P, Hewison C, Khan U, Huerga H, Seung KJ, et al. Culture conversion in patients treated with bedaquiline and/or delamanid. A prospective multicountry study. Am J Respir Crit Care Med. 2021;203(1):111–9. https://doi.org/10.1164/rccm.202001-0135OC.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  83. Pontali E, Sotgiu G, Tiberi S, Tadolini M, Visca D, D’Ambrosio L, et al. Combined treatment of drug-resistant tuberculosis with bedaquiline and delamanid: a systematic review. Eur Respir J. 2018;52(1) https://doi.org/10.1183/13993003.00934-2018.

  84. Dooley KE, Rosenkranz SL, Conradie F, Moran L, Hafner R, von Groote-Bidlingmaier F, et al. QT effects of bedaquiline, delamanid, or both in patients with rifampicin-resistant tuberculosis: a phase 2, open-label, randomised, controlled trial. Lancet Infect Dis. 2021;21(7):975–83. https://doi.org/10.1016/S1473-3099(20)30770-2.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  85. Nunn AJ, Phillips PPJ, Meredith SK, Chiang CY, Conradie F, Dalai D, et al. A trial of a shorter regimen for rifampin-resistant tuberculosis. N Engl J Med. 2019;380(13):1201–13. https://doi.org/10.1056/NEJMoa1811867.

    Article  CAS  PubMed  Google Scholar 

  86. Khan PY, Franke MF, Hewison C, Seung KJ, Huerga H, Atwood S, et al. All-oral longer regimens are effective for the management of multidrug-resistant tuberculosis in high-burden settings. Eur Respir J. 2022;59(1):2004345. https://doi.org/10.1183/13993003.04345-2020.

    Article  CAS  PubMed  Google Scholar 

  87. World Health Organization. Rapid communication: key changes to the treatment of drug-resistant tuberculosis. Geneva: World Health Organization; 2022.

    Google Scholar 

  88. Conradie F ED, Olugbosi M, Wills G, Fabiane S, Timm J, Spigelman M. High rate of successful outcomes treating highly resistant TB in the ZeNix study of pretomanid, bedaquiline, and alternative doses and duration of linezolid. Conference abstract: International AIDS Society. 2021.

    Google Scholar 

  89. Haley CA, Macias P, Jasuja S, Jones BA, Rowlinson MC, Jaimon R, et al. Novel 6-month treatment for drug-resistant tuberculosis, United States. Emerg Infect Dis. 2021;27(1):332–4. https://doi.org/10.3201/eid2701.203766.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  90. Centers for Disease Control and Prevention. Provisional CDC guidance for the use of pretomanid as part of a regimen [bedaquiline, pretomanid, and linezolid (BPaL)] to treat drug-resistant tuberculosis disease. Atlanta: Centers for Disease Control and Prevention; 2022.

    Google Scholar 

  91. Xu HB, Jiang RH, Li L. Pulmonary resection for patients with multidrug-resistant tuberculosis: systematic review and meta-analysis. J Antimicrob Chemother. 2011;66(8):1687–95. https://doi.org/10.1093/jac/dkr210.

    Article  CAS  PubMed  Google Scholar 

  92. Kempker RR, Vashakidze S, Solomonia N, Dzidzikashvili N, Blumberg HM. Surgical treatment of drug-resistant tuberculosis. Lancet Infect Dis. 2012;12(2):157–66. https://doi.org/10.1016/S1473-3099(11)70244-4.

    Article  PubMed  PubMed Central  Google Scholar 

  93. Pomerantz BJ, Cleveland JC Jr, Olson HK, Pomerantz M. Pulmonary resection for multi-drug resistant tuberculosis. J Thorac Cardiovasc Surg. 2001;121(3):448–53. https://doi.org/10.1067/mtc.2001.112339.

    Article  CAS  PubMed  Google Scholar 

  94. Fox GJ, Mitnick CD, Benedetti A, Chan ED, Becerra M, Chiang CY, et al. Surgery as an adjunctive treatment for multidrug-resistant tuberculosis: an individual patient data metaanalysis. Clin Infect Dis. 2016;62(7):887–95. https://doi.org/10.1093/cid/ciw002.

    Article  PubMed  Google Scholar 

  95. Bastos ML, Lan Z, Menzies D. An updated systematic review and meta-analysis for treatment of multidrug-resistant tuberculosis. Eur Respir J. 2017;49(3):1600803. https://doi.org/10.1183/13993003.00803-2016.

    Article  PubMed  Google Scholar 

  96. Johnston JC, Shahidi NC, Sadatsafavi M, Fitzgerald JM. Treatment outcomes of multidrug-resistant tuberculosis: a systematic review and meta-analysis. PLoS One. 2009;4(9):e6914. https://doi.org/10.1371/journal.pone.0006914.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  97. Orenstein EW, Basu S, Shah NS, Andrews JR, Friedland GH, Moll AP, et al. Treatment outcomes among patients with multidrug-resistant tuberculosis: systematic review and meta-analysis. Lancet Infect Dis. 2009;9(3):153–61. https://doi.org/10.1016/S1473-3099(09)70041-6.

    Article  PubMed  Google Scholar 

  98. Jacobson KR, Tierney DB, Jeon CY, Mitnick CD, Murray MB. Treatment outcomes among patients with extensively drug-resistant tuberculosis: systematic review and meta-analysis. Clin Infect Dis. 2010;51(1):6–14. https://doi.org/10.1086/653115.

    Article  PubMed  Google Scholar 

  99. Kempker RR, Smith AGC, Avaliani T, Gujabidze M, Bakuradze T, Sabanadze S, et al. Cycloserine and linezolid for tuberculosis meningitis: pharmacokinetic evidence of potential usefulness. Clin Infect Dis. 2021; https://doi.org/10.1093/cid/ciab992.

  100. Donald PR. Cerebrospinal fluid concentrations of antituberculosis agents in adults and children. Tuberculosis (Edinb). 2010;90(5):279–92. https://doi.org/10.1016/j.tube.2010.07.002.

    Article  CAS  PubMed  Google Scholar 

  101. Tucker EW, Pieterse L, Zimmerman MD, Udwadia ZF, Peloquin CA, Gler MT, et al. Delamanid central nervous system pharmacokinetics in tuberculous meningitis in rabbits and humans. Antimicrob Agents Chemother. 2019;63(10):e00913–9. https://doi.org/10.1128/AAC.00913-19.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  102. Seddon JA, Hesseling AC, Marais BJ, McIlleron H, Peloquin CA, Donald PR, et al. Paediatric use of second-line anti-tuberculosis agents: a review. Tuberculosis (Edinb). 2012;92(1):9–17. https://doi.org/10.1016/j.tube.2011.11.001.

    Article  CAS  PubMed  Google Scholar 

  103. Ettehad D, Schaaf HS, Seddon JA, Cooke GS, Ford N. Treatment outcomes for children with multidrug-resistant tuberculosis: a systematic review and meta-analysis. Lancet Infect Dis. 2012;12(6):449–56. https://doi.org/10.1016/S1473-3099(12)70033-6.

    Article  PubMed  Google Scholar 

  104. World Health Organization. Rapid communication on updated guidance on the management of tuberculosis in children and adolescents. Geneva: World Health Organization; 2021.

    Google Scholar 

  105. World Health Organization. WHO consolidated guidelines on tuberculosis. Module 5: management of tuberculosis in children and adolescents. Geneva: World Health Organization; 2022.

    Google Scholar 

  106. Alene KA, Jegnie A, Adane AA. Multidrug-resistant tuberculosis during pregnancy and adverse birth outcomes: a systematic review and meta-analysis. BJOG. 2021;128(7):1125–33. https://doi.org/10.1111/1471-0528.16573.

    Article  CAS  PubMed  Google Scholar 

  107. Walt MV, Masuku S, Botha S, Nkwenika T, Keddy KH. Retrospective record review of pregnant women treated for rifampicin-resistant tuberculosis in South Africa. PLoS One. 2020;15(9):e0239018. https://doi.org/10.1371/journal.pone.0239018.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  108. Loveday M, Hughes J, Sunkari B, Master I, Hlangu S, Reddy T, et al. Maternal and infant outcomes among pregnant women treated for multidrug/rifampicin-resistant tuberculosis in South Africa. Clin Infect Dis. 2021;72(7):1158–68. https://doi.org/10.1093/cid/ciaa189.

    Article  PubMed  Google Scholar 

  109. Gandhi NR, Moll A, Sturm AW, Pawinski R, Govender T, Lalloo U, et al. Extensively drug-resistant tuberculosis as a cause of death in patients co-infected with tuberculosis and HIV in a rural area of South Africa. Lancet. 2006;368(9547):1575–80. https://doi.org/10.1016/S0140-6736(06)69573-1.

    Article  PubMed  Google Scholar 

  110. Abdool Karim SS, Naidoo K, Grobler A, Padayatchi N, Baxter C, Gray AL, et al. Integration of antiretroviral therapy with tuberculosis treatment. N Engl J Med. 2011;365(16):1492–501. https://doi.org/10.1056/NEJMoa1014181.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  111. Havlir DV, Kendall MA, Ive P, Kumwenda J, Swindells S, Qasba SS, et al. Timing of antiretroviral therapy for HIV-1 infection and tuberculosis. N Engl J Med. 2011;365(16):1482–91. https://doi.org/10.1056/NEJMoa1013607.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  112. Blanc FX, Sok T, Laureillard D, Borand L, Rekacewicz C, Nerrienet E, et al. Earlier versus later start of antiretroviral therapy in HIV-infected adults with tuberculosis. N Engl J Med. 2011;365(16):1471–81. https://doi.org/10.1056/NEJMoa1013911.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  113. Mfinanga SG, Kirenga BJ, Chanda DM, Mutayoba B, Mthiyane T, Yimer G, et al. Early versus delayed initiation of highly active antiretroviral therapy for HIV-positive adults with newly diagnosed pulmonary tuberculosis (TB-HAART): a prospective, international, randomised, placebo-controlled trial. Lancet Infect Dis. 2014;14(7):563–71. https://doi.org/10.1016/S1473-3099(14)70733-9.

    Article  PubMed  Google Scholar 

  114. Luetkemeyer AF, Kendall MA, Nyirenda M, Wu X, Ive P, Benson CA, et al. Tuberculosis immune reconstitution inflammatory syndrome in A5221 STRIDE: timing, severity, and implications for HIV-TB programs. J Acquir Immune Defic Syndr. 2014;65(4):423–8. https://doi.org/10.1097/QAI.0000000000000030.

    Article  CAS  PubMed  Google Scholar 

  115. Torok ME, Yen NT, Chau TT, Mai NT, Phu NH, Mai PP, et al. Timing of initiation of antiretroviral therapy in human immunodeficiency virus (HIV)—associated tuberculous meningitis. Clin Infect Dis. 2011;52(11):1374–83. https://doi.org/10.1093/cid/cir230.

    Article  PubMed  Google Scholar 

  116. 2022. https://clinicalinfo.hiv.gov/en/guideline/adult-andd-adolescent-opportunistic-infection/

  117. Kurbatova EV, Gammino VM, Bayona J, Becerra M, Danilovitz M, Falzon D, et al. Frequency and type of microbiological monitoring of multidrug-resistant tuberculosis treatment. Int J Tuberc Lung Dis. 2011;15(11):1553–5, i. https://doi.org/10.5588/ijtld.11.0101.

    Article  CAS  PubMed  Google Scholar 

  118. Lan Z, Ahmad N, Baghaei P, Barkane L, Benedetti A, Brode SK, et al. Drug-associated adverse events in the treatment of multidrug-resistant tuberculosis: an individual patient data meta-analysis. Lancet Respir Med. 2020;8(4):383–94. https://doi.org/10.1016/S2213-2600(20)30047-3.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  119. Schnippel K, Firnhaber C, Berhanu R, Page-Shipp L, Sinanovic E. Adverse drug reactions during drug-resistant TB treatment in high HIV prevalence settings: a systematic review and meta-analysis. J Antimicrob Chemother. 2017;72(7):1871–9. https://doi.org/10.1093/jac/dkx107.

    Article  CAS  PubMed  Google Scholar 

  120. Wu S, Zhang Y, Sun F, Chen M, Zhou L, Wang N, et al. Adverse events associated with the treatment of multidrug-resistant tuberculosis: a systematic review and meta-analysis. Am J Ther. 2016;23(2):e521–30. https://doi.org/10.1097/01.mjt.0000433951.09030.5a.

    Article  PubMed  Google Scholar 

  121. Hwang TJ, Dotsenko S, Jafarov A, Weyer K, Falzon D, Lunte K, et al. Safety and availability of clofazimine in the treatment of multidrug and extensively drug-resistant tuberculosis: analysis of published guidance and meta-analysis of cohort studies. BMJ Open. 2014;4(1):e004143. https://doi.org/10.1136/bmjopen-2013-004143.

    Article  PubMed  PubMed Central  Google Scholar 

  122. Gopal M, Padayatchi N, Metcalfe JZ, O’Donnell MR. Systematic review of clofazimine for the treatment of drug-resistant tuberculosis. Int J Tuberc Lung Dis. 2013;17(8):1001–7. https://doi.org/10.5588/ijtld.12.0144.

    Article  CAS  PubMed  Google Scholar 

  123. Hwang TJ, Wares DF, Jafarov A, Jakubowiak W, Nunn P, Keshavjee S. Safety of cycloserine and terizidone for the treatment of drug-resistant tuberculosis: a meta-analysis. Int J Tuberc Lung Dis. 2013;17(10):1257–66. https://doi.org/10.5588/ijtld.12.0863.

    Article  CAS  PubMed  Google Scholar 

  124. Zhang X, Falagas ME, Vardakas KZ, Wang R, Qin R, Wang J, et al. Systematic review and meta-analysis of the efficacy and safety of therapy with linezolid containing regimens in the treatment of multidrug-resistant and extensively drug-resistant tuberculosis. J Thorac Dis. 2015;7(4):603–15. https://doi.org/10.3978/j.issn.2072-1439.2015.03.10.

    Article  PubMed  PubMed Central  Google Scholar 

  125. Agyeman AA, Ofori-Asenso R. Efficacy and safety profile of linezolid in the treatment of multidrug-resistant (MDR) and extensively drug-resistant (XDR) tuberculosis: a systematic review and meta-analysis. Ann Clin Microbiol Antimicrob. 2016;15(1):41. https://doi.org/10.1186/s12941-016-0156-y.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  126. Sotgiu G, D’Ambrosio L, Centis R, Tiberi S, Esposito S, Dore S, et al. Carbapenems to treat multidrug and extensively drug-resistant tuberculosis: a systematic review. Int J Mol Sci. 2016;17(3):373. https://doi.org/10.3390/ijms17030373.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  127. Hewison C, Khan U, Bastard M, Lachenal N, Coutisson S, Osso E, et al. Safety of treatment regimens containing bedaquiline and delamanid in the endTB cohort. Clin Infect Dis. 2022; https://doi.org/10.1093/cid/ciac019.

  128. Marks SM, Mase SR, Morris SB. Systematic review, meta-analysis, and cost-effectiveness of treatment of latent tuberculosis to reduce progression to multidrug-resistant tuberculosis. Clin Infect Dis. 2017;64(12):1670–7. https://doi.org/10.1093/cid/cix208.

    Article  PubMed  Google Scholar 

  129. Fox GJ, Oxlade O, Menzies D. Fluoroquinolone therapy for the prevention of multidrug-resistant tuberculosis in contacts. A cost-effectiveness analysis. Am J Respir Crit Care Med. 2015;192(2):229–37. https://doi.org/10.1164/rccm.201501-0069OC.

    Article  CAS  PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. National Jewish Health, Denver, CO, USA

    Charles L. Daley

  2. University of Colorado, School of Medicine, Aurora, CO, USA

    Charles L. Daley

Authors
  1. Charles L. Daley
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Charles L. Daley .

Editor information

Editors and Affiliations

  1. Respiratory Medicine, NHO Ibarakihigashi National Hosp, Ibaraki, Japan

    Takefumi Saito

  2. Division of Pulmonary, Critical Care and Sleep Medicine, University of Washington, Seattle, WA, USA

    Masahiro Narita

  3. National Jewish Health, Denver, CO, USA

    Charles L. Daley

Rights and permissions

Reprints and permissions

Copyright information

© 2022 The Author(s), under exclusive license to Springer Nature Singapore Pte Ltd.

About this chapter

Check for updates. Verify currency and authenticity via CrossMark

Cite this chapter

Daley, C.L. (2022). Advances in Treatment of Drug-Resistant Pulmonary TB: What Is the Latest Approach to Treat Drug-Resistant Pulmonary TB?. In: Saito, T., Narita, M., Daley, C.L. (eds) Pulmonary Tuberculosis and Its Prevention. Respiratory Disease Series: Diagnostic Tools and Disease Managements. Springer, Singapore. https://doi.org/10.1007/978-981-19-3995-2_7

Download citation

  • DOI: https://doi.org/10.1007/978-981-19-3995-2_7

  • Published:

  • Publisher Name: Springer, Singapore

  • Print ISBN: 978-981-19-3994-5

  • Online ISBN: 978-981-19-3995-2

  • eBook Packages: MedicineMedicine (R0)

Publish with us

Policies and ethics

Search

Navigation